There are various concepts with premature ejaculation. There lacks a universally acknowledged definition of premature ejaculation. According to DSM-IV-TR (Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition, Text Revision), it defines premature ejaculation as the persistent or recurrent onset of orgasm and ejaculation with minimal sexual stimulation before, during, or shortly after penetration and before the person wishes it.
Premature ejaculation is recognized to be the most common male sexual disorder, affecting approximately 30% of men. This prevalence rate is three times higher than that of erectile dysfunction (Int J Impot Res 2005 17:39-57). Erectile dysfunction is common in middle-aged men as well as in older men, whereas premature ejaculation occurs in men of all ages and has a deleterious impact on quality of life. Premature ejaculation is generally classified as either primary or secondary. Primary form applies to men who have had the condition since they became capable of functioning sexually (i.e., post-puberty). Primary premature ejaculation (PE) is associated with changes of neurotransmitters, which are involved in a variety of psychological actions. Secondary PE is considered when an individual has been able to control his ejaculation and faced no problem earlier but later is unable to do so due to mental stress, erectile dysfunction, prostatitis, urethritis or drug administration.
The two main causes contributing to premature ejaculation are biological and psychogenic factors. Biological factors include penile hypersensitivity, hyperexcitability of ejaculatory reflex, increased sexual arousability, endocrinopathy, genetic predisposition, and 5-HT receptor dysfunction. Psychogenic risk factors include anxiety, early sexual experiences, ejaculatory control techniques, and psychodynamics (J Sex Med 2004 1:58-65).
The ejaculatory process is mediated by a complex interplay of neurotransmitters, such as 5-hydroxytryptamine (5-HT) and dopamine. Cholinergic, adrenergic, GA-BAnergic and oxytocinergic neurons have also been shown to be involved in the regulation of ejaculation. Of these, 5-HT has been known to play a major role in the regulation of ejaculation (Urology 2003 61:623-628). The overall role of serotonin (5-HT) on ejaculation has been shown to be inhibitory (Physiol Behav 2004 83:291-307). 5-HT released at L3-L5 spinal segments from terminals of axons descending from the rostral region of the paragigantocellular nucleus (nPGi) in the brainstem exerts an inhibitory role on ejaculation (Exp Brain Res 1992 88:313-320). Also, ejaculation is inhibited when 5-HT is released from serotonergic neurons in the medial preoptic area (MPOA), which is a hypothalamic brain area. (Eur J Pharmacol 1992 210:121-129). Serotonin is released from presynaptic neurons and acts on receptors on postsynaptic neurons in which 5-HT2C receptor mediates the effects of serotonin on ejaculation. Presynaptic 5-HT1B and somatodendritic 5-HT 1A autoreceptors induce a negative feedback control over 5-HT release and prevent over-stimulation of postsynaptic 5-HT receptors to inhibit ejaculation. Then, 5-HT molecules present in the synapse are taken up again back into the presynaptic neuron via 5-HT transporter, which is located on the cell bodies of the presynaptic neuron. In this way, 5-HT is implicated in the control of ejaculation (European Urology 2006 50:454-466).
There are non-drug treatment and drug treatment for premature ejaculation.
Non-drug treatment for premature ejaculation is equally said behavioral therapies. The most popular methods are the squeeze technique developed by Masters & Johnson (1970) and the stop-start technique developed by Semans (1956). However, there are problems with the two techniques in terms that they are time-consuming and require the proper participation of his partner, leading to difficulty in practice and low success rates (Contemp Urol 2001 13:51-59).
No drug is approved by the American FDA for the treatment of premature ejaculation. However, many studies have shown that topical anesthetics, off-label use of antidepressants, and the like are effective to treat premature ejaculation. The most commonly used topical anesthetic cream to desensitize the head of the penis is EMLA cream or spray that contains lidocaine and prilocaine. The lidocaine-prilocaine formulation has been shown to be in part effective in premature ejaculation and to improve sexual satisfaction when applied 30 minutes before sexual intercourse, but causes decreased penile sensation and vaginal numbness in a female partner (Int J Impot Res 2003 15:277-281). A domestically developed SS cream, which is prepared with an extract from nine Chinese herbal medicines, significantly increases intra vaginal ejaculation latency time (IVELT) in a clinical trial, but it is currently not marketed due to its low effectiveness and side effects including local burning and pain (Yonsei Med J 1997 38:91-95).
Tricyclic antidepressants (TCAs) and selective serotonin reuptake inhibitors (SSRIs) are currently used off-label. TCAs are less selective for inhibition of serotonin reuptake and have more side effects than SSRIs (Contemp Urol 2001 13:51-59).
SSRIs, such as Fluoxetine, paroxetine, sertraline, citalopram and fluvoxamine, have been shown to be effective in treating premature ejaculation. In particular, U.S. Pat. No. 4,136,193 discloses anti-depressive 1-dimethylaminopropyl-1-phenylphthalans, which comprise the citalopram compound that is similar to compounds according to the present invention. When various doses and administration schemes were tested, continuous daily administration of SSRI over a 2-wk period prolonged IVELT by 3-10 minutes and was thus more effective in premature ejaculation than a single dosing before intercourse (J Urol 1998 159:1935-1938).
However, the long-term use of SSRIs increases the incidence of side effects such as vomiting, dry mouth, drowsiness, reduced libido and an ejaculation (J Sex Marital Ther 1999 25:89-101). With respect to effectiveness, SSRIs have another decisive drawback of having no indication for their use in premature ejaculation treatment. Moreover, SSRIs are intended for chronic use rather than on-demand use because they have a long half-life and a long Tmax, which is the time to maximal plasma concentration, and it takes a long time for SSRIs to exert their therapeutic effects or efficacies, and these are difficult to predict.
When SSRI drugs are used in combination with monoamine oxidase inhibitors such as lithium, sumatriptan and tryptophan, there is an increased risk of serotonin syndrome with side effects including fever, delirium, coma, sweating and dizziness (N Eng J Med 2005 352:1112-1120).
In this regard, the inventors of the present application conducted intensive and thorough research in order to develop a compound that has a good ejaculation-delaying effect, an about three times shorter half-life and better safety and is thus suitable for on-demand use in premature ejaculation treatment. The research resulted in the findings that novel 1,3-dihydro-5-isobenzofurancarbonitrile derivatives or pharmaceutically acceptable salts thereof have a good ejaculation-delaying effect with a short half-life, thereby leading to the present invention.